The present invention relates to the use of certain pharmaceutical compounds as antidepressants.
Compounds having NMDA (N-methyl-D-aspartate) antagonist activity are known in the art, for example see Watkins et al., Trends in Pharmacological Science, 11:25, 1990.
In particular, certain compounds are disclosed in EP 279 937 and EP 633 879 as having NMDA antagonist activity and as being useful for treating various CNS disorders such as epilepsy. It has now surprisingly been found that the low affinity NMDA antagonist compounds of EP 633 879 as exemplified by (S)-1-phenyl-2-(2-pyridyl)ethanamine, have activity in the mouse forced swim test, indicating that such compounds are potentially useful as antidepressant agents. In particular, low affinity NMDA antagonists such as (S)-1-phenyl-2-(2-pyridyl)ethanamine are expected to be useful in the treatment of depression associated with neurodegenerative disorders such as Alzheimer""s disease. The compound (S)-1-phenyl-2-(2-pyridyl)ethanamine is particularly advantageous in that neither stimulation nor sedation are observed as side effects.
In a first aspect the invention therefore provides the use of a low affinity NMDA antagonist for the treatment of depression.
Particularly suitable compounds include the compounds known as memantine, budipine, amantidine, 5-aminocarbonyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine, dextromethorphan and NPS 1506, and the compounds disclosed in EP 279 937 and EP 633 879.
Preferred compounds include compounds of formula (I): 
wherein:
R1 is pyridyl, phenyl or 4-fluorophenyl;
R2 is phenyl or 4-fluorophenyl;
R3 is hydrogen, C1-6 alkyl or methoxycarbonyl;
R4 is hydrogen or methyl; and
R5 is hydrogen or COCH2NH2,
and metabolites thereof, both as free bases and pharmaceutically acceptable salts thereof.
Preferably the compound of formula (I) is 1-phenyl-2-(2-pyridyl)ethanamine or a pharmaceutically acceptable salt thereof, more preferably the (S) isomer.
A further preferred compound is 2-amino-N-(1,2-diphenyl-1-methylethyl)acetamide (Remacemide; EP 279 937) or a pharmaceutically acceptable salt or metabolite thereof.
The present invention includes compounds of formula (I) in the form of salts, in particular acid addition salts. Suitable salts include all known pharmaceutically acceptable salts including those formed with both organic and inorganic acids. Thus, preferred salts include those formed from hydrochloric, hydrobromic, sulphuric, phosphoric, citric, tartaric, lactic, pyruvic, acetic, succinic, fumaric, maleic, methanesulphonic and benzenesulphonic acids. Hydrochloride salts are particularly preferred.
Substance P antagonists are active in models of depression and may have clinical use in treating depression. Whilst not wishing to be restricted by theory, this implies that Substance P may play a role in the etiology of depression. Substance P is released by stimulation of the NMDA receptor. Therefore, NMDA antagonists may act as antidepressants by inhibition of the release of substance P. Low-affinity use-dependent
NMDA antagonists may be particularly effective in treating depression that is associated with diseases such as Alzheimer""s disease, Parkinson""s disease, stroke, dementia, coronary bypass disease and any other disease in which excitatory amino acids such as glutamate are involved. Therefore the invention also provides a method of treating or preventing depression, including depression associated with the above disorders, which comprises administering to a person in need thereof a therapeutically effective amount of a low affinity NMDA antagonist or a pharmaceutically acceptable salt thereof.
In a further aspect the invention provides a low affinity NMDA antagonist, in particular a compound of formula (I), in the manufacture of a medicament for use in the prevention or treatment of the above disorders, in particular for the treatment or prophylaxis of depression.
Suitable daily dose ranges are from about 0.5 mg/kg to about 5 mg/kg. Unit doses may be administered conventionally once or more than once a day; for example, 2, 3, or 4 times a day; more usually 1 or 2 times a day. A typical dosing regime would be oral, once or twice a day at 30, 60, 120 or 150 mg.
The pharmaceutical composition comprising the compound of the invention may conveniently be tablets, pills, capsules, syrups, powders or granules for oral administration; sterile parental or subcutaneous solutions, suspensions for parental administration; or suppositories for rectal administration; all of which are well known in the art.